Transposable elements (TEs) are repetitive DNA sequences that originate from ancient viruses and currently make up nearly half of the human genome. While TEs were once labeled as “junk” DNA with no functional significance, recent research has found that they act as genetic switches, controlling the activity of nearby genes in specific cell types. Proper classification and annotation of TEs is critical for understanding their evolution, co-option, regulatory roles, and potential impact on the host.
In a new study published in Science Advances titled “A phylogenetic approach uncovers cryptic endogenous retrovirus subfamilies in the primate lineage,” researchers from Kyoto University have developed an annotation approach based on phylogenetic analysis and cross-species conservation to reveal the regulatory roles of TEs in human development. The study was led by co-corresponding authors Xun Chen, PhD, assistant professor at Kyoto University; Guillaume Bourque, PhD, professor in the Department of Human Genetics at McGill University; and Fumitaka Inoue, PhD, associate professor at Kyoto University.
Many TEs were integrated into the primate genomes after the divergence from other mammals. TEs have contributed a substantial number of regulatory sequences to the human genome and are associated with the evolution of TF-binding sites during primate evolution. The study focused on the poorly categorized, young long terminal repeat (LTR) subfamilies known as MER11A/B/C.
Results revealed the presence of four “new subfamilies,” suggesting a new annotation for approximately 20% these repeat elements. Notably, the intermediate-aged MER11_G2/G3 contained multiple transcription factor motifs, such as ZIC, which plays a role in embryonic development, and TEAD, implicated in cell proliferation. These TF motifs were conserved between human and macaque, suggesting a functional role during the early expansion of MER11, and before the divergence between these two species. The authors also applied their approach across 53 simian-enriched LTR subfamilies, and defined 75 new subfamilies with novel annotation for approximately 30% of instances from 26 subfamilies.
To directly test whether MER11 sequences can control gene expression, the authors validated the regulatory potential of these subfamilies using lentivirus-based massively parallel reporter assay (lentiMPRA), a novel technology that enables functional characterization of enhancers in a high-throughput and quantitative manner by using transcribed barcodes, on nearly 7000 MER11 sequences and identified motifs associated with their differential activities.
Results showed that the youngest subfamily, MER11_G4, exhibited a strong ability to activate gene expression. Further analysis indicated that MER11_G4 sequences in humans, chimpanzees, and macaques had each accumulated different changes over time. For example, some sequences gained mutations that increased their regulatory potential during stem cells in humans and chimpanzees.
Human MER11_G4 was found to possess a SOX motif deletion, which emerged after the divergence between humans and macaques. SOX15 and SOX17 are known to play crucial roles in human primordial germ cell differentiation and tissue-specific gene regulation. The authors suggest that these ape-specific SOX motifs in MER11 subfamilies may influence the gene regulatory network during development in a lineage-specific manner.
Looking ahead, the authors stated that using epigenetic and functional profiles, as in this study, could be an effective strategy to evaluate alternative methods for TE classification and annotation.
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